The present invention relates to novel piperazine derivatives, methods of use and pharmaceutical compositions containing them.
The compounds of the invention are potent and selective inhibitors of chemokine binding to its receptor CCR1 found on inflammatory and immunomodulatory cells (preferably leukocytes and lymphocytes). The CCR1 receptor is also sometimes referred to as the CC-CKR1 receptor. These compounds also inhibit MIP-1xcex1 (and the related chemokines shown to interact with CCR1 (e.g., RANTES and MCP-3)) induced chemotaxis of THP-1 cells and human leukocytes and are potentially useful for the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), lupus, inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), chronic bronchitis, xeno-transplantation, transplantation tissue rejection (chronic and acute), organ transplant rejection (chronic and acute), atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis) and sequelae associated with certain cancers such as multiple myeloma. Compounds in this series may also limit the production of cytokines at inflammatory sites, including but not limited to TNF and IL-1, as a consequence of decreasing cell infiltration, providing benefit for diseases linked to TNF and IL-1, including congestive heart failure, pulmonary emphysema or dyspnea associated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex). They may also provide benefit for the sequelae associated with infection where such infection induces production of detrimental inflammatory cytokines such as TNF e.g, fungal meningitis, joint tissue damage, hyperplasia, pannus formation and bone resorption, psoriatic arthritis, hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardial infarction, acute liver failure, lyme disease, septic shock, cancer, trauma, and malaria.
MIP-1xcex1 and RANTES are soluble chemotactic peptides (chemokines) which are produced by inflammatory cells, in particular CD8+ lymphocytes, polymorphonuclear leukocytes (PMNs) and macrophages, J. Biol. Chem., 270 (30) 29671-29675 (1995). These chemokines act by inducing the migration and activation of key inflammatory and immunomodulatory cells. Elevated levels of chemokines have been found in the synovial fluid of rheumatoid arthritis patients, chronic and acute rejecting tissue from transplant patients and in the nasal secretions of allergic rhinitis patients following allergen exposure (Teran, et al., J. Immunol., 1806-1812 (1996), and Kuna et al., J. Allergy Clin. Immunol. 321 (1994)). Antibodies which interfere with the chemokine/receptor interaction by neutralizing MIP1xcex1 or gene disruption have provided direct evidence for the role of MIP-1xcex1 and RANTES in disease by limiting the recruitment of monocytes and CD8+ lymphocytes (Smith et al., J. Immunol, 153, 4704 (1994) and Cook et al., Science, 269, 1583 (1995)). Together this data demonstrates that CCR1 receptor antagonists would be an effective treatment of several immune based diseases. The compounds described within are potent and selective antagonists of the CCR1 receptor.
The present invention also relates to a compound of the formula 
or the pharmaceutically acceptable salt thereof; wherein
a is 1, 2, 3, 4 or 5;
b is 0, 1, 2, 3 or 4;
c is 0 or 1;
d is 1, 2, 3, 4 or 5;
e is 0 or 1;
j is 1, 2, 3, or 4;
X is C(O), C(S) or CH2;
Y is CH2, or if e is 0, Y is CHR8 wherein R8 is hydrogen, (C6-C10)aryl or NR9R10;
Z is oxygen, NR9 or CR11R12;
each R1 is independently selected from hydrogen, hydroxy, hydroxysulfonyl, halo, (C1-C6)alkyl, mercapto, mercapto(C1-C6)alkyl, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsufonyl, (C1-C6)alkylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkoxy, (C6-C10)aryloxy, halo(C1-C6)alkyl, trifluoromethyl, formyl, formyl(C1-C6)alkyl, nitro, nitroso, cyano, (C6-C10)aryl(C1-C6)alkoxy, halo(C1-C6)alkoxy, trifluoromethoxy, (C3-C7)cycloalkyl, (C3-C7)cycloalkyl(C1-C6)alkyl, hydroxy(C3-C7)cycloalkyl(C1-C6)alkyl, (C3-C7)cycloalkylamino, (C3-C7)cycloalkylamino(C1-C6)alkyl, ((C3-C7)cycloalkyl)((C1-C6)alkyl)amino, ((C3-C7)cycloalkyl(C1-C6)alkyl)amino(C1-C6)alkyl, cyano(C1-C6)alkyl, (C2-C7)alkenyl, (C2-C7)alkynyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, hydroxy(C1-C6)alkyl, hydroxy(C6-C10)aryl(C1-C6)alkyl, hydroxy(C1-C6)alkylthio(C1-C6)alkyl, hydroxy(C2-C6)alkenyl, hydroxy(C2-C6)alkynyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C6-C10)arylamino, (C6-C10)aryl(C1-C6)alkylamino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkyl, hydroxy(C1-C6)alkylamino(C1-C6)alkyl, (C6-C10)acylamino(C1-C6)alkyl, (C6-C10)aryl (C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylcarbonylamino, ((C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino, (C1-C6)alkylcarbonylamino(C1-C6)alkyl, ((C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino, (C1-C6)alkoxycarbonyl)(C1-C6)alkylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonyl)((C1-C6)alkyl)amino(C1-C6)alkyl,
, (C1-C6)alkoxycarbonyl, (C6-C10)aryl(C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C6-C10)arylcarbonyl, (C6-C10)arylcarbonyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkylcarbonyl, (C6-C10)aryl(C1-C6)alkycarbonyl(C1-C6)alkyl, carboxy(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxycarbonyl(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkylcarbonyloxy(C1-C6)alkyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, ((C1-C6)alkyl)2aminocarbonyl, (C6-C10)arylaminocarbonyl, (C6-C10)aryl(C1-C6)alkylaminocarbonyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkyl, (C6-C10)arylaminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, amidino, guanidino, ureido, (C1-C6)alkylureido, ((C1-C6)alkyl)2ureido, ureido(C1-C6)alkyl, (C1-C6)alkylureido(C1-C6)alkyl, ((C1-C6)alkyl)2ureido(C1-C6)alkyl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl(C1-C6)alkyl and (C2-C9)heteroaryl(C1-C6)alkyl;
each R2 and R3 are independently selected from oxo, halo, (C1-C6)alkyl, (C3-C8)cycloalkyl, (C3-C8)cycloalkyl(C1-C6)alkyl, (C3-C8)cycloalkylamino(C1-C6)alkyl, (C3-C8)cycloalkyl(C1-C6)alkylamino(C1-C6)alkyl, halo(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, Hxe2x80x94C(O)xe2x80x94, Hxe2x80x94C(O)xe2x80x94(C1-C6)alkyl, hydroxy(C1-C6)alkyl, hydroxy(C2-C6)alkenyl, hydroxy(C2-C6)alkynyl, hydroxy(C6-C10)aryl(C1-C6)alkyl, hydroxy(C3-C8)cycloalkyl(C1-C6)alkyl, thio(C1-C6)alkyl, cyano(C1-C6)alkyl, halo(C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C1-C6)alkoxy(C6-C10)aryl(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, (C6-C10)aryloxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, hydroxy(C1-C6)alkylthio(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkyl, (C6-C10)arylamino(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylcarbonylamino(C1-C6)alkyl, azido(C1-C6)alkyl, aminocarbonylamino(C1-C6)alkyl, (C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2aminocarbonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonyl (C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkyl, hydroxy(C1-C6)alkylamino(C1-C6)alkyl, (C6-C10)aryloxy(C1-C6)alkylcarbonyloxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkylcarbonyloxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkylcarbonyloxy(C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, carboxy, (C1-C6)alkoxycarbonyl, (C6-C10)aryl(C1-C6)alkoxycarbonyl, (C6-C10)aryl(C1-C6)alkylcarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, ((C1-C6)alkyl)2aminocarbonyl, (C6-C10)arylaminocarbonyl, (C6-C10)aryl(C1-C6)alkylaminocarbonyl, carboxy(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxycarbonyl(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkyl, (C6-C10)arylaminocarbonyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, (C6-C10)arylsulfonyl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl or R14R15N(C1-C6)alkyl wherein R14 and R15 are each independently (C1-C6)alkyl or (C1-C6)alkylcarbonyl;
R4 is (R5)f(R6)g(C6-C10)aryl, (R5)f(R6)g(C3-C10)cycloalkyl, (R5)f(R7)h(C2-C9)heteroaryl, or (R5)f(R7)h(C2-C9)heterocycloalkyl,
wherein f is 1, 2, 3 or 4;
g and h are each independently 0, 1, 2 or 3;
R5 is one to three groups independently selected from (C2-C9)heterocycloalkylcarbonyl, (C2-C9)heteroarylcarbonyl, (C2-C9)heteroaryl(C1-C6)alkylaminocarbonyl, (C2-C9)heterocycloalkyl(C1-C6)alkylaminocarbonyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylaminocarbonyl, ureido(C1-C6)alkylaminocarbonyl, (C1-C6)alkylureido(C1-C6)alkylaminocarbonyl, ((C1-C6)alkyl)2ureido(C1-C6)alkylaminocarbonyl, halo(C1-C6)alkylaminocarbonyl, aminosulfonyl(C1-C6)alkylaminocarbonyl, (C1-C6)alkylaminosulfonyl(C1-C6)alkylaminocarbonyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylcarbonylamino, cyanoguanidino(C1-C6)alkylcarbonylamino, (C1-C6)alkylcyanoguanidino(C1-C6)alkylcarbonylamino, ((C1-C6)alkyl)2cyanoguanidino(C1-C6)alkylcarbonylamino, aminocarbonyl(C1-C6)alkylcarbonylamino, (C2-C9)heteroaryl(C1-C6)alkylcarbonylamino, (C2-C9)heterocycloalkyl(C1-C6)alkylcarbonylamino, aminosulfonyl(C1-C6)alkylcarbonylamino, hydroxy(C1-C6)alkylureido, amino(C1-C6)alkylureido, (C1-C6)alkylamino(C1-C6)alkylureido, ((C1-C6)alkyl)2amino(C1-C6)alkylureido, (C2-C9)heterocycloalkyl(C1-C6)alkylureido, (C2-C9)heteroaryl(C1-C6)alkylureido, aminosulfonyl(C1-C6)alkylureido, aminocarbonyl(C1-C6)alkylureido, (C1-C6)alkylaminocarbonyl(C1-C6)alkylureido, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkylureido, acetylamino(C1-C6)alkylureido, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylureido, halo(C1-C6)alkylsulfonylamino, amino(C1-C6)alkylsulfonylamino, (C1-C6)alkylamino(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2amino(C1-C6)alkylsulfonylamino, acetylamino(C1-C6)alkylsulfonylamino, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylsulfonylamino, ureido(C1-C6)alkylsulfonylamino, (C1-C6)alkylureido(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2ureido(C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylsulfonylamino, cyanoguanidino(C1-C6)alkylsulfonylamino, (C1-C6)alkylcyanoguanidino(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2cyanoguanidino(C1-C6)alkylsulfonylamino, aminocarbonyl(C1-C6)alkylsulfonylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkylsulfonylamino, aminosulfonylamino, (C1-C6)alkylaminosulfonylamino, ((C1-C6)alkyl)2aminosulfonylamino, aminocarbonyl(C1-C6)alkylamino(C1-C6)alkylsulfonylamino, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylsulfonylamino, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylsulfonylamino, cyanoguanidino, (C1-C6)alkylcyanoguanidino, ((C1-C6)alkyl)2cyanoguanidino, (C2-C9)heterocycloalkylcyanoguanidino, (C2-C9)heteroarylcyanoguanidino, (C2-C9)heterocycloalkyl(C1-C6)alkylcyanoguanidino, (C2-C9)heteroaryl(C1-C6)alkylcyanoguanidino, amino(C1-C6)alkylcyanoguanidino, (C1-C6)alkylamino(C1-C6)alkylcyanoguanidino, ((C1-C6)alkyl)2amino(C1-C6)alkylcyanoguanidino, aminocarbonyl(C1-C6)alkylcyanoguanidino, (C1-C6)alkylaminocarbonyl(C1-C6)alkylcyanoguanidino, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkylcyanoguanidino, aminocarbonyl(C1-C6)alkylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkylamino, aminosulfonyl(C1-C6)alkylamino, (C2-C9)heteroaryl(C1-C6)alkylamino, acetylamino(C1-C6)alkylamino, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl(C1-C6)alkylamino(C1-C6)alkyl, cyano(C1-C6)alkylaminoalkyl, aminocarbonyl(C1-C6)alkylamino(C1-C6)alkyl, acetylamino(C1-C6)alkylamino(C1-C6)alkyl, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkylamino(C1-C6)alkyl, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylamino(C1-C6)alkyl, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylamino(C1-C6)alkyl, cyanoguanidino(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylcyanoguanidino(C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2cyanoguanidino(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylamino(C1-C6)alkyl, ureido(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylureido(C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2ureido(C1-C6)alkylamino(C1-C6)alkyl, aminocarbonyloxy(C1-C6)alkylamino(C1-C6)alkyl, aminocarbonyl(C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkylcarbonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkylcarbonylamino(C1-C6)alkyl, aminosulfonyl(C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkyl, cyanoguanidino(C1-C6)alkylcarbonylamino(C1-C6)alkyl, cyano(C1-C6)alkylcarbonylamino(C1-C6)alkyl, amino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, hydroxy(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, aminocarbonyl(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C1-C6)alkylcarbonylamino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, ureido(C1-C6)alkylureido(C1-C6)alkyl, (C1-C6)alkylureido(C1-C6)alkylureido(C1-C6)alkyl, ((C1-C6)alkyl)2ureido(C1-C6)alkylureido(C1-C6)alkyl, cyanoguanidino(C1-C6)alkylureido(C1-C6)alkyl, halo(C1-C6)alkylsulfonylamino(C1-C6)alkyl, amino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, acetylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, ureido(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylureido(C1-C6)alkylsulfonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2ureido(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, cyanoguanidino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkyl(cyanoguanidino)(C1-C6)alkylsulfonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2(cyanoguanidino)(C1-C6)alkylsulfonylamino(C1-C6)alkyl, aminocarbonyl(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, aminosulfonylamino(C1-C6)alkyl, (C1-C6)alkylaminosulfonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2aminosulfonylamino(C1-C6)alkyl, cyanoguanidino(C1-C6)alkyl, (C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, ((C1-C6)alkyl)2(cyanoguanidino)(C1-C6)alkyl, (C2-C9)heterocycloalkyl(cyanoguanidino)(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, (C2-C9)heterocycloalkyl(cyanoguanidino)amino, (C2-C9)heteroaryl(cyanoguanidino)(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, amino(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl, (C2-C9)heterocycloalkylsulfonyl, amino(C1-C6)alkylaminosulfonyl, (C1-C6)alkylamino(C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2amino(C1-C6)alkylaminosulfonyl, (C2-C9)heteroarylaminosulfonyl, hydroxy(C1-C6)alkylaminosulfonyl, (C1-C6)alkoxy(C1-C6)alkylaminosulfonyl, ureido(C1-C6)alkylaminosulfonyl, (C1-C6)alkylureido(C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2ureido(C1-C6)alkylaminosulfonyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylaminosulfonyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkylaminosulfonyl, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylaminosulfonyl, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylaminosulfonyl, aminocarbonyl(C1-C6)alkylaminosulfonyl, cyanoguanidino(C1-C6)alkylaminosulfonyl, (C2-C9)heteroaryl(C1-C6)alkylaminosulfonyl, (C2-C9)heterocycloalkylaminosulfonyl, R6 is one to three groups independently selected from hydrogen, hydroxy, hydroxysulfonyl, halo, (C1-C6)alkyl, mercapto, mercapto(C1-C6)alkyl, (C1-C6)alkylthio, (C1-C6)alkylsulfinyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, (C1-C6)alkylthio(C1-C6)alkyl, (C1-C6)alkylsulfinyl(C1-C6)alkyl, (C1-C6)alkylsulfonyl(C1-C6)alkyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkoxy, (C6-C10)aryloxy, halo(C1-C6)alkyl, trifluoro(C1-C6)alkyl, formyl, formyl(C1-C6)alkyl, nitro, nitroso, cyano, (C6-C10)aryl(C1-C6)alkoxy, halo(C1-C6)alkoxy, trifluoro(C1-C6)alkoxy, amino(C1-C6)alkoxy, (C3-C10)cycloalkyl, (C3-C10)cycloalkyl(C1-C6)alkyl, hydroxy(C3-C10)cycloalkyl(C1-C6)alkyl, (C3-C10)cycloalkylamino, (C3-C10)cycloalkylamino(C1-C6)alkyl, cyano(C1-C6)alkyl, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C6-C10)aryl(C2-C6)alkenyl, hydroxy(C1-C6)alkyl, (hydroxy) (C6-C10)aryl(C1-C6)alkyl, ((C1-C6)alkylamino)(C6-C10)aryl(C1-C6)alkyl, hydroxy(C1-C6)alkylthio(C1-C6)alkyl, hydroxy(C2-C6)alkenyl, hydroxy(C2-C6)alkenyl, hydroxy(C2-C6)alkynyl, (C1-C6)alkoxy(C1-C6)alkyl, (C1-C6)alkoxy(C6-C10)aryl(C1-C6)alkyl, aryloxy(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C6-C10)arylamino, (C6-C10)aryl(C1-C6)alkylamino, amino(C1-C6)alkylamino, (C2-C9)heterocycloalkylamino, (C2-C9)heteroarylamino, (C3-C10)cycloalkyl(C1-C6)alkyl)amino, (C1-C6)alkylcarbonylamino, (C1-C6)alkoxycarbonylamino, (C2-C6)alkenylcarbonylamino, (C3-C10)cycloalkylcarbonylamino, (C6-C10)arylcarbonylamino, (C2-C9)heterocycloalkylcarbonylamino, halo(C1-C6)alkylcarbonylamino, (C1-C6)alkoxy(C1-C6)alkylcarbonylamino, (C1-C6)alkoxycarbonyl(C1-C6)alkylcarbonylamino, ((C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino, ((C1-C6)alkoxycarbonyl)((C1-C6)alkyl)amino, (C1-C6)alkylsulfonylamino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkyl, hydroxy(C1-C6)alkylamino(C1-C6)alkyl, (C6-C10)arylamino(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C6-C10)arylcarbonylamino(C1-C6)alkyl, ((C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino(C1-C6)alkyl, C3-C10)cycloalkyl(C1-C6)alkyl)amino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkylcarbonylamino(C1-C6)alkyl, ((C1-C6)alkoxycarbonyl)((C1-C6)alkyl)amino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, ((C1-C6)alkylsulfonyl)((C1-C6)alkyl)amino(C1-C6)alkyl, (C6-C10)arylsulfonylamino(C1-C6)alkyl, ((C6-C10)arylsulfonyl)((C1-C6)alkyl)amino(C1-C6)alkyl, (C2-C9)heterocycloalkylamino(C1-C6)alkyl, (C2-C9)heteroarylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C6-C10)aryl(C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, (C6-C10)arylcarbonyl, (C6-C10)aryl(C1-C6)alkylcarbonyl, hydroxy(C1-C6)alkoxycarbonyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkoxycarbonyl(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkylcarbonyloxy(C1-C6)alkyl, ((C1-C6)alkyl)2aminocarbonyloxy(C1-C6)alkyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C6-C10)arylcarbonyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkylcarbonyl(C1-C6)alkyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, ((C1-C6)alkyl)2aminocarbonyl, (C6-C10)arylaminocarbony), (C6-C10)aryl(C1-C6)alkylaminocarbonyl, (aminocarbonyl(C1-C6)alkylaminocarbonyl, ((C1-C6)alkylaminocarbonyl(C1-C6)alkylaminocarbonyl, ((C1-C6)alkoxycarbonyl(C1-C6)alkylaminocarbonyl, (amino(C1-C6)alkyl)aminocarbonyl, (hydroxy(C1-C6)alkylaminocarbonyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkyl, (C6-C10)arylaminocarbonyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkylaminocarbonyl(C1-C6)alkyl, amidino, hydroxyamidino, guanidino, ureido, (C1-C6)alkylureido, (C6-C10)arylureido, ((C6-C10)aryl)2ureido, (C6-C10)aryl(C1-C6)alkylureido, halo(C1-C6)alkylureido, ((C1-C6)alkyl)((C6-C10)aryl)ureido, ((C1-C6)alkyl)2ureido, halo(C1-C6)alkylcarbonylureido, ureido(C1-C6)alkyl, (C1-C6)alkylureido(C1-C6)alkyl, ((C1-C6)alkyl)2ureido(C1-C6)alkyl, (C6-C10)arylureido(C1-C6)alkyl, (C6-C10)aryl)2ureido(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkylureido(C1-C6)alkyl, halo(C1-C6)alkylureido(C1-C6)alkyl, (halo(C1-C6)alkyl)((C1-C6)alkyl)ureido(C1-C6)alkyl, ((C1-C6)alkoxycarbonyl (C1-C6)alkyl)ureido(C1-C6)alkyl, glycinamido, (C1-C6)alkylglycinamido, aminocarbonylglycinamido, (C1-C6)alkoxy(C1-C6)alkylcarbonylglycinamido, (aminocarbonyl)((C1-C6)alkyl)glycinamido, ((C1-C6)alkoxycarbonyl(C1-C6)alkylcarbonyl)((C1-C6)alkyl)glycinamido, ((C1-C6)alkoxycarbonylamino(C1-C6)alkylcarbonyl)glycinamido, (C6-C10)arylcarbonylglycinamido, ((C6-C10)arylcarbonyl)((C1-C6)alkyl)glycinamido, ((C6-C10)aryl(C1-C6)alkylaminocarbonyl)glycinamido, (C6-C10)aryl(C1-C6)alkylaminocarbonyl)((C1-C6)alkyl)glycinamido, (C6-C10)arylaminocarbonylglycinamido, ((C6-C10)arylaminocarbonyl)((C1-C6)alkyl)glycinamido, glycinamido(C1-C6)alkyl, alaninamido, (C1-C6)alkylalaninamido, alaninamido(C1-C6)alkyl, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl, (C2-C9)heteroaryl(C1-C6)alkyl and (C2-C9)heterocycloalkyl(C1-C6)alkyl;
R7 is one to three groups independently selected from hydrogen, hydroxy, halo, (C1-C6)alkyl, (C1-C6)alkylsulfonyl, (C6-C10)arylsulfonyl, (C1-C6)alkoxy, hydroxy(C1-C6)alkoxy, halo(C1-C6)alkyl, formyl, nitro, cyano, halo(C1-C6)alkoxy, (C2-C6)alkenyl, (C2-C6)alkynyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C6-C10)arylamino, (C6-C10)aryl(C1-C6)alkylamino, (C1-C6)alkylcarbonylamino, (C1-C6)alkoxycarbonylamino, (C2-C6)alkenylcarbonylamino, cycloalkylcarbonylamino, (C6-C10)arylcarbonylamino, halo(C1-C6)alkylcarbonylamino, (C1-C6)alkoxy(C1-C6)alkylcarbonylamino, (C1-C6)alkoxycarbonyl(C1-C6)alkylcarbonylamino, ((C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino, ((C1-C6)alkoxycarbonyl)((C1-C6)alkyl)amino, (C1-C6)alkylsulfonylamino, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkyl, (C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C6-C10)arylcarbonylamino(C1-C6)alkyl, ((C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonyl, (C6-C10)aryl(C1-C6)alkoxycarbonyl, (C1-C6)alkylcarbonyl, (C6-C10)arylcarbonyl, (C6-C10)aryl(C1-C6)alkylcarbonyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, ((C1-C6)alkyl)2aminocarbonyl, (C6-C10)arylaminocarbonyl, aminocarbonyl(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkyl, (C6-C10)arylaminocarbonyl(C1-C6)alkyl, guanidino, ureido, (C1-C6)alkylureido, ureido(C1-C6)alkyl, (C1-C6)alkylureido(C1-C6)alkyl, and glycinamido;
R9 and R10 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, (C1-C6)alkylcarbonyl, (C1-C6)alkylcarbonyl(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkylcarbonyl, (C6-C10)aryl(C1-C6)alkylcarbonyl(C1-C6)alkyl, aminocarbonyl, (C1-C6)alkylaminocarbonyl, ((C1-C6)alkyl)2aminocarbonyl and (C1-C6)alkoxycarbonyl; and
R11 and R12 are each independently selected from the group consisting of hydrogen, (C1-C6)alkyl, (C6-C10)aryl, (C6-C10)aryl(C1-C6)alkyl, hydroxy, (C1-C6)alkoxy, hydroxy(C1-C6)alkyl, (C1-C6)alkoxy(C1-C6)alkyl, amino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C1-C6)alkylcarbonylamino, (C3-C8)cycloalkylcarbonylamino, (C3-C8)cycloalkyl(C1-C6)alkylcarbonylamino, (C1-C6)alkoxycarbonylamino, (C1-C6)alkylsulfonylamino, (C6-C10)arylcarbonylamino, (C1-C6)alkoxycarbonyl(C1-C6)alkylcarbonylamino, (C6-C10)aryl(C1-C6)alkylcarbonylamino, ((C6-C10)aryl(C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino, (C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C3-C8)cycloalkylcarbonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkyl, (C2-C9)heterocycloalkylcarbonylamino(C1-C6)alkyl, (C6-C10)aryl(C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C2-C9)heteroarylcarbonylamino(C1-C6)alkyl, (C6-C10)arylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkyl, aminocarbonylamino, (C1-C6)alkylaminocarbonylamino, halo(C1-C6)alkylaminocarbonylamino, ((C1-C6)alkyl)2aminocarbonylamino, aminocarbonylamino(C1-C6)alkyl, (C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2aminocarbonylamino(C1-C6)alkyl, halo(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, amino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkyl, carboxy(C1-C6)alkyl, (C1-C6)alkoxycarbonyl(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl and (C1-C6)alkylaminocarbonyl(C1-C6)alkyl.
Preferred compounds of formula I include those wherein R1 is hydrogen, halo, cyano, nitro, trifluoromethyl, trifluoromethoxy, (C1-C6)alkyl, hydroxy or (C1-C6)alkylcarbonyloxy.
Other preferred compounds of formula I include those wherein R2 and R3 are each independently selected from (C1-C6)alkyl, (C3-C8)cycloalkyl, amino(C1-C6)alkyl, amino(C3-C8)cycloalkyl, (C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylamino(C3-C8)cycloalkyl, hydroxy(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkyl, ureido(C1-C6)alkyl, (C1-C6)alkyureido(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl or (C2-C9)heterocycloalkyl (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein c is 1; X is C(O), d is 1; Y is CH2; e is 1; and Z is oxygen.
Other preferred compounds of formula I include those wherein c is 1; X is C(O); d is 2; Y is ethylene; and e is 0.
Other preferred compounds of formula I include those wherein c is 1; X is C(O); d is 1; Y is CH2; e is 1; and Z is NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein c is 1; X is CH2; d is 1; Y is CH2; e is 1; and Z is oxygen.
Other preferred compounds of formula I include those wherein c is 1; X is CH2; d is 2; Y is ethylene; and e is 0.
Other preferred compounds of formula I include those wherein c is 1; X is CH2; d is 1; Y is CH2; e is 1, and Z is NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein c is 1; X is C(O); d is 1; Y is CHR8 wherein R8 is NR9R10; R9 and R10 are each independently hydrogen, (C1-C6)alkyl or (C1-C6)alkylcarbonyl; e is 1; and Z is oxygen.
Other preferred compounds of formula I include those wherein c is 1; X is C(O); d is 1; Y is CHR8 wherein R8 is NR9R10; R9 and R10 are each independently hydrogen, (C1-C6)alkyl or (C1-C6)alkylcarbonyl; e is 1; and Z is CR11R12 wherein R11 and R12 are hydrogen.
Other preferred compounds of formula I include those wherein c is 1; X is C(O); d is 1; Y is CHR8 wherein R8 is NR9R10; R9 and R10 are each independently hydrogen, (C1-C6)alkyl or (C1-C6)alkylcarbonyl; e is 1; and Z is NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein c is 1; X is CH2; d is 1; Y is CHR8 wherein R8 is NR9R10; R9 and R10 are each independently hydrogen, (C1-C6)alkyl or (C1-C6)alkylcarbonyl; e is 1; and Z is oxygen.
Other preferred compounds of formula I include those wherein c is 1; X is CH2; d is 1; Y is CHR8 wherein R8 is NR9R10; R9 and R10 are each independently hydrogen, (C1-C6)alkyl or (C1-C6)alkylcarbonyl; e is 1; and Z is CR11R12 wherein R11 and R12 are hydrogen.
Other preferred compounds of formula I include those wherein c is 1; X is CH2; d is 1; Y is CHR8 wherein R8 is NR9R10; R9 and R10 are each independently hydrogen, (C1-C6)alkyl or (C1-C6)alkylcarbonyl; e is 1; and Z is NR9 wherein R9 is hydrogen or (C1-C6)alkyl.
Other preferred compounds of formula I include those wherein R4 is (R5)f(R6)g(C6-C10)aryl or (R5)f(R7)h(C2-C9)heteroaryl wherein f, g and h are independently 1 or 2.
Other preferred compounds of formula I include those wherein R5 is (C2-C9)heterocycloalkylcarbonyl, (C2-C9)heteroarylcarbonyl, (C2-C9)heteroaryl(C1-C6)alkylaminocarbonyl, (C2-C9)heterocycloalkyl(C1-C6)alkylaminocarbonyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylaminocarbonyl, ureido(C1-C6)alkylaminocarbonyl, (C1-C6)alkylureido(C1-C6)alkylaminocarbonyl, ((C1-C6)alkyl)2ureido(C1-C6)alkylaminocarbonyl, aminosulfonyl(C1-C6)alkylaminocarbonyl or (C1-C6)alkylaminosulfonyl(C1-C6)alkylaminocarbonyl.
Other preferred compounds of formula I include those wherein R5 is (C1-C6)alkylsulfonylamino(C1-C6)alkylcarbonylamino, cyanoguanidino(C1-C6)alkylcarbonylamino, (C1-C6)alkylcyanoguanidino(C1-C6)alkylcarbonylamino, ((C1-C6)alkyl)2cyanoguanidino(C1-C6)alkylcarbonylamino, aminocarbonyl(C1-C6)alkylcarbonylamino, (C2-C9)heteroaryl(C1-C6)alkylcarbonylamino, (C2-C9)heterocycloalkyl(C1-C6)alkylcarbonylamino, or aminosulfonyl(C1-C6)alkylcarbonylamino.
Other preferred compounds of formula I include those wherein R5 is amino(C1-C6)alkylureido, (C1-C6)alkylamino(C1-C6)alkylureido, ((C1-C6)alkyl)2amino(C1-C6)alkylureido, (C2-C9)heterocycloalkyl(C1-C6)alkylureido, (C2-C9)heteroaryl(C1-C6)alkylureido, aminosulfonyl(C1-C6)alkylureido, aminocarbonyl(C1-C6)alkylureido, (C1-C6)alkylaminocarbonyl(C1-C6)alkylureido, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkylureido, acetylamino(C1-C6)alkylureido, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylureido.
Other preferred compounds of formula I include those wherein R5 is amino(C1-C6)alkylsulfonylamino, (C1-C6)alkylamino(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2amino(C1-C6)alkylsulfonylamino, acetylamino(C1-C6)alkylsulfonylamino, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylsulfonylamino, ureido(C1-C6)alkylsulfonylamino, (C1-C6)alkylureido(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2ureido(C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylsulfonylamino, cyanoguanidino(C1-C6)alkylsulfonylamino, (C1-C6)alkylcyanoguanidino(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2cyanoguanidino(C1-C6)alkylsulfonylamino, aminocarbonyl(C1-C6)alkylsulfonylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkylsulfonylamino, aminosulfonylamino, (C1-C6)alkylaminosulfonylamino, ((C1-C6)alkyl)2aminosulfonylamino, aminocarbonyl(C1-C6)alkylamino(C1-C6)alkylsulfonylamino, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylsulfonylamino or (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylsulfonylamino.
Other preferred compounds of formula I include those wherein R5 is cyanoguanidino, (C1-C6)alkylcyanoguanidino, ((C1-C6)alkyl)2cyanoguanidino, (C2-C9)heterocycloalkylcyanoguanidino, (C2-C9)heteroarylcyanoguanidino, (C2-C9)heterocycloalkyl(C1-C6)alkylcyanoguanidino, (C2-C9)heteroaryl(C1-C6)alkylcyanoguanidino, amino(C1-C6)alkylcyanoguanidino, (C1-C6)alkylamino(C1-C6)alkylcyanoguanidino, ((C1-C6)alkyl)2amino(C1-C6)alkylcyanoguanidino, aminocarbonyl(C1-C6)alkylcyanoguanidino, (C1-C6)alkylaminocarbonyl(C1-C6)alkylcyanoguanidino or ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkylcyanoguanidino.
Other preferred compounds of formula I include those wherein R5 is aminocarbonyl(C1-C6)alkylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkylamino, aminosulfonyl(C1-C6)alkylamino, (C2-C9)heteroaryl(C1-C6)alkylamino, acetylamino(C1-C6)alkylamino or (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylamino.
Other preferred compounds of formula I include those wherein R5 is cyano(C1-C6)alkylaminoalkyl or aminocarbonyl(C1-C6)alkylamino(C1-C6)alkyl.
Other preferred compounds of formula I include those wherein R5 is acetylamino(C1-C6)alkylamino(C1-C6)alkyl, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkylamino(C1-C6)alkyl, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylamino(C1-C6)alkyl, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylamino(C1-C6)alkyl, cyanoguanidino(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylcyanoguanidino(C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2cyanoguanidino(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylamino(C1-C6)alkyl, ureido(C1-C6)alkylamino(C1-C6)alkyl, (C1-C6)alkylureido(C1-C6)alkylamino(C1-C6)alkyl, ((C1-C6)alkyl)2ureido(C1-C6)alkylamino(C1-C6)alkyl or aminocarbonyloxy(C1-C6)alkylamino(C1-C6)alkyl.
Other preferred compounds of formula I include those wherein R5 is acetylamino(C1-C6)alkylcarbonylamino(C1-C6)alkyl, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylcarbonylamino(C1-C6)alkyl, aminocarbonyl(C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkylcarbonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkylcarbonylamino(C1-C6)alkyl, aminosulfonyl(C1-C6)alkylcarbonylamino(C1-C6)alkyl, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkyl, cyanoguanidino(C1-C6)alkylcarbonylamino(C1-C6)alkyl or cyano(C1-C6)alkylcarbonylamino(C1-C6)alkyl.
Other preferred compounds of formula I include those wherein R5 is amino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkylaminocarbonyl amino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, aminocarbonyl(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C1-C6) alkylcarbonylamino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonyl amino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C2-C9)heterocycloalkyloxycarbonyl amino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, ureido(C1-C6)alkylureido(C1-C6)alkyl, (C1-C6)alkylureido(C1-C6)alkylureido(C1-C6)alkyl, ((C1-C6)alkyl)2ureido(C1-C6)alkylureido(C1-C6)alkyl or cyanoguanidino(C1-C6)alkylureido(C1-C6)alkyl.
Other preferred compounds of formula I include those wherein R5 is amino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, acetylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, ureido(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylureido(C1-C6)alkylsulfonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2ureido(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, cyanoguanidino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkyl(cyanoguanidino)(C1-C6)alkylsulfonylamino(C1-C6)alkyl, ((C1-C6)alkyl)2(cyanoguanidino)(C1-C6)alkylsulfonylamino(C1-C6)alkyl, aminocarbonyl(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylsulfonylamino(C1-C6)alkyl, aminosulfonylamino(C1-C6)alkyl, (C1-C6)alkylaminosulfonylamino(C1-C6)alkyl or ((C1-C6)alkyl)2aminosulfonylamino(C1-C6)alkyl.
Other preferred compounds of formula I include those wherein R5 is cyanoguanidino(C1-C6)alkyl, (C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, ((C1-C6)alkyl)2(cyanoguanidino)(C1-C6)alkyl, (C2-C9)heterocycloalkyl(cyanoguanidino)(C1-C6)alkyl, (C2-C9)heteroaryl(cyanoguanidino)(C1-C6)alkyl, (C2-C9)heterocycloalkyl(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, (C2-C9)heteroaryl(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, amino(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, (C1-C6)alkylamino(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, ((C1-C6)alkyl)2amino(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, aminocarbonyl(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl, (C1-C6)alkylaminocarbonyl(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl or ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkyl(cyanoguanidino)(C1-C6)alkyl.
Other preferred compounds of formula I include those wherein R5 is (C2-C9)heterocycloalkylsulfonyl, amino(C1-C6)alkylaminosulfonyl, (C1-C6)alkylamino(C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2amino(C1-C6)alkylaminosulfonyl, (C2-C9)heteroarylaminosulfonyl, ureido(C1-C6)alkylaminosulfonyl, (C1-C6)alkylureido(C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2ureido(C1-C6)alkylaminosulfonyl, (C1-C6)alkylsulfonylamino(C1-C6)alkylaminosulfonyl, (C1-C6)alkoxycarbonylamino(C1-C6)alkylaminosulfonyl, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylaminosulfonyl, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylaminosulfonyl, aminocarbonyl(C1-C6)alkylaminosulfonyl, cyanoguanidino(C1-C6)alkylaminosulfonyl, (C2-C9)heteroaryl(C1-C6)alkylaminosulfonyl, (C2-C9)heterocycloalkylaminosulfonyl, Other preferred compounds of formula I include those wherein R5 is halo(C1-C6)alkylaminocarbonyl, hydroxy(C1-C6)alkylureido, halo(C1-C6)alkylsulfonylamino, (C1-C6)alkoxycarbonyl(C1-C6)alkylamino(C1-C6)alkyl, hydroxy(C1-C6)alkylaminocarbonylamino(C1-C6)alkyl, halo(C1-C6)alkylsulfonylamino(C1-C6)alkyl, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl, hydroxy(C1-C6)alkylaminosulfonyl, and (C1-C6)alkoxy(C1-C6)alkylaminosulfonyl.
Other preferred compounds of formula I include those wherein R6 and R7 are each independently halo, halo(C1-C6)alkyl, (C1-C6)alkyl, (C1-C6)alkoxy, trifluoromethyl, trifluoromethoxy, hydroxy, aminocarbonyl, cyano, ureido, (C1-C6)alkylsulfonylamino, (C1-C6)alkoxycarbonylamino or glycinamino.
The present invention also relates to the pharmaceutically acceptable acid addition salts of compounds of the formula I. The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the aforementioned base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as the hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate, bisulfate, phosphate, acid phosphate, acetate, lactate, citrate, acid citrate, tartrate, bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)]salts.
The invention also relates to base addition salts of formula I. The chemical bases that may be used as reagents to prepare pharmaceutically acceptable base salts of those compounds of formula I that are acidic in nature are those that form non-toxic base salts with such compounds. Such non-toxic base salts include, but are not limited to those derived from such pharmacologically acceptable cations such as alkali metal cations (e.g., potassium and sodium) and alkaline earth metal cations (e.g., calcium and magnesium), ammonium or water-soluble amine addition salts such as N-methylglucamine-(meglumine), and the lower alkanolammonium and other base salts of pharmaceutically acceptable organic amines.
The compounds of this invention may contain olefin-like double bonds. When such bonds are present, the compounds of the invention exist as cis and trans configurations and as mixtures thereof.
The present invention also relates to compounds of formula I wherein any of the hydrogens may optionally be replaced by deuterium.
Unless otherwise indicated, the alkyl, alkenyl and alkynyl groups referred to herein, as well as the alkyl moieties of other groups referred to herein (e.g., alkoxy), may be linear or branched, and they may also be cyclic (e.g., cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl) or be linear or branched and contain cyclic moieties. Unless otherwise indicated, halogen includes fluorine, chlorine, bromine, and iodine.
(C3-C10)Cycloalkyl when used herein refers to cycloalkyl groups containing zero to two levels of unsaturation such as cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, 1,3-cyclohexadiene, cycloheptyl, cycloheptenyl, bicyclo[3.2.1]octane, norbornanyl etc.
(C2-C9)Heterocycloalkyl when used herein refers to pyrrolidinyl, tetrahydrofuranyl, dihydrofuranyl, tetrahydropyranyl, pyranyl, thiopyranyl, aziridinyl, oxiranyl, methylenedioxyl, chromenyl, barbituryl, isoxazolidinyl, 1,3-oxazolidin-3-yl, isothiazolidinyl, 1,3-thiazolidin-3-yl, 1,2-pyrazolidin-2-yl, 1,3-pyrazolidin-1-yl, piperidinyl, thiomorpholinyl, 1,2-tetrahydrothiazin-2-yl, 1,3-tetrahydrothiazin-3-yl, tetrahydrothiadiazinyl, morpholinyl, 1,2-tetrahydrodiazin-2-yl, 1,3-tetrahydrodiazin-1-yl, tetrahydroazepinyl, piperazinyl, or chromanyl.
(C2-C9)Heteroaryl when used herein refers to furyl, thienyl, thiazolyl, pyrazolyl, isothiazolyl, oxazolyl, isoxazolyl, pyrrolyl, triazolyl, tetrazolyl, imidazolyl, 1,3,5-oxadiazolyl, 1,2,4-oxadiazolyl, 1,2,3-oxadiazolyl, 1,3,5-thiadiazolyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, pyridyl, pyrimidyl, pyrazinyl, pyridazinyl, 1,2,4-triazinyl, 1,2,3-triazinyl, 1,3,5-triazinyl, pyrazolo[3,4-b]pyridinyl, cinnolinyl, pteridinyl, purinyl, 6,7-dihydro-5H-[1]pyrindinyl, benzo[b]thiophenyl, 5,6,7,8-tetrahydro-quinolin-3-yl, benzoxazolyl, benzothiazolyl, benzisothiazolyl, benzisoxazolyl, benzimidazolyl, thianaphthenyl, isothianaphthenyl, benzofuranyl, isobenzofuranyl, isoindolyl, indolyl, indolizinyl, indazolyl, isoquinolyl, quinolyl, phthalazinyl, quinoxalinyl, quinazolinyl, or benzoxazinyl.
Aryl when used herein refers to phenyl or naphthyl.
The term xe2x80x9cureidoxe2x80x9d, as used herein, refers to an xe2x80x9camino-carbonyl-aminoxe2x80x9d moiety.
The term xe2x80x9cacetylxe2x80x9d, as used herein, refers to an xe2x80x9calkyl-carbonylxe2x80x9d moiety wherein alkyl is defined as above.
The term xe2x80x9ccyanoguanidinoxe2x80x9d, as used herein, refers to a functional group having the following formula 
The term xe2x80x9c(C2-C9)heterocycloalkyl(Cxe2x95x90Nxe2x80x94CN)aminoxe2x80x9d, as used herein refers to a functional group having the following formula 
wherein xe2x80x9cHETxe2x80x9d refers to a (C2-C9)heterocyloalkyl or (C2-C9)heteroaryl group and the nitrogen of said group is the place of attachment.
The term xe2x80x9cmercaptoxe2x80x9d, as used herein, refers to a xe2x80x9cHS-xe2x80x9d moeity.
The compounds of this invention include all conformational isomers (e.g., cis and trans isomers) and all optical isomers of compounds of the formula I (e.g., enantiomers and diastereomers), as well as racemic, diastereomeric and other mixtures of such isomers.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from autoimmune diseases, rheumatoid arthritis, recent onset type I diabetes, lupus, inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, vasculitis, acute and chronic inflammatory conditions, osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, glomerulonephritis, allergic conditions, asthma, atopic dermatitis, infection associated with inflammation, viral inflammation, influenza, hepatitis, Guillian-Barre, chronic bronchitis, xeno-transplantation, chronic and acute transplantation tissue rejection, chronic and acute organ transplant rejection, atherosclerosis, restenosis, HIV infectivity, granulomatous diseases, sarcoidosis, leprosy and tuberculosis and sequelae associated with certain cancers such as multiple myeloma. Compounds in this series may also limit the production of cytokines at inflammatory sites, including but not limited to TNF and IL-1, as a consequence of decreasing cell infiltration, providing benefit for diseases linked to TNF and IL-1, including congestive heart failure, pulmonary emphysema or dyspnea associated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex). They may also provide benefit for the sequelae associated with infection where such infection induces production of detrimental inflammatory cytokines such as TNF e.g, fungal meningitis, joint tissue damage, hyperplasia, pannus formation and bone resorption, psoriatic arthritis, hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardial infarction, acute liver failure, lyme disease, septic shock, cancer, trauma, and malaria in a mammal, preferably a human, comprising an amount of a compound of the formula I or a pharmaceutically acceptable salt thereof effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by inhibiting chemokine binding to the receptor CCR1 in a mammal, preferably a human, comprising an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, effective in treating or preventing such disorder or condition and a pharmaceutically acceptable carrier Examples of such disorders and conditions are those enumerated in the preceding paragraph.
The present invention also relates to a method for treating or preventing a disorder or condition selected from autoimmune diseases, rheumatoid arthritis, recent onset type I diabetes, lupus, inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, vasculitis, acute and chronic inflammatory conditions, osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, glomerulonephritis, allergic conditions, asthma, atopic dermatitis, infection associated with inflammation, viral inflammation, influenza, hepatitis, Guillian-Barre, chronic bronchitis, xeno-transplantation, chronic and acute transplantation tissue rejection, chronic and acute organ transplant rejection, atherosclerosis, restenosis, HIV infectivity, granulomatous diseases, sarcoidosis, leprosy and tuberculosis and sequelae associated with certain cancers such as multiple myeloma. Compounds in this series may also limit the production of cytokines at inflammatory sites, including but not limited to TNF and IL-1, as a consequence of decreasing cell infiltration, providing benefit for diseases linked to TNF and IL-1, including congestive heart failure, pulmonary emphysema or dyspnea associated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex). They may also provide benefit for the sequelae associated with infection where such infection induces production of detrimental inflammatory cytokines such as TNF e.g, fungal meningitis, joint tissue damage, hyperplasia, pannus formation and bone resorption, psoriatic arthritis, hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardial infarction, acute liver failure, lyme disease, septic shock, cancer, trauma, and malaria in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition.
The present invention also relates to a method for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention an amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, that is effective in treating or preventing such disorder or condition.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition selected from autoimmune diseases, rheumatoid arthritis, recent onset type I diabetes, lupus, inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, vasculitis, acute and chronic inflammatory conditions, osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, glomerulonephritis, allergic conditions, asthma, atopic dermatitis, infection associated with inflammation, viral inflammation, influenza, hepatitis, Guillian-Barre, chronic bronchitis, xeno-transplantation, chronic and acute transplantation tissue rejection, chronic and acute organ transplant rejection, atherosclerosis, restenosis, HIV infectivity, granulomatous diseases, sarcoidosis, leprosy and tuberculosis and sequelae associated with certain cancers such as multiple myeloma. Compounds in this series may also limit the production of cytokines at inflammatory sites, including but not limited to TNF and IL-1, as a consequence of decreasing cell infiltration, providing benefit for diseases linked to TNF and IL-1, including congestive heart failure, pulmonary emphysema or dyspnea associated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex). They may also provide benefit for the sequelae associated with infection where such infection induces production of detrimental inflammatory cytokines such as TNF e.g, fungal meningitis, joint tissue damage, hyperplasia, pannus formation and bone resorption, psoriatic arthritis, hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardial infarction, acute liver failure, lyme disease, septic shock, cancer, trauma, and malaria in a mammal, preferably a human, comprising a CCR1 receptor antagonizing effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a pharmaceutical composition for treating or preventing a disorder or condition that can be treated or prevented by antagonizing the CCR1 receptor in a mammal, preferably a human, comprising a CCR1 receptor antagonizing effective amount of a compound of the formula I, or a pharmaceutically acceptable salt thereof, and a pharmaceutically acceptable carrier.
The present invention also relates to a method for treating or preventing a disorder or condition selected from autoimmune diseases, rheumatoid arthritis, recent onset type I diabetes, lupus, inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, vasculitis, acute and chronic inflammatory conditions, osteoarthritis, adult Respiratory Distress Syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, glomerulonephritis, allergic conditions, asthma, atopic dermatitis, infection associated with inflammation, viral inflammation, influenza, hepatitis, Guillian-Barre, chronic bronchitis, xeno-transplantation, chronic and acute transplantation tissue rejection, chronic and acute organ transplant rejection, atherosclerosis, restenosis, HIV infectivity, granulomatous diseases, sarcoidosis, leprosy and tuberculosis and sequelae associated with certain cancers such as multiple myeloma. Compounds in this series may also limit the production of cytokines at inflammatory sites, including but not limited to TNF and IL-1, as a consequence of decreasing cell infiltration, providing benefit for diseases linked to TNF and IL-1, including congestive heart failure, pulmonary emphysema or dyspnea associated therewith, emphysema; HIV-1, HIV-2, HIV-3; cytomegalovirus (CMV), adenoviruses, Herpes viruses (Herpes zoster and Herpes simplex). They may also provide benefit for the sequelae associated with infection where such infection induces production of detrimental inflammatory cytokines such as TNF e.g, fungal meningitis, joint tissue damage, hyperplasia, pannus formation and bone resorption, psoriatic arthritis, hepatic failure, bacterial meningitis, Kawasaki syndrome, myocardial infarction, acute liver failure, lyme disease, septic shock, cancer, trauma, and malaria in a mammal, preferably a human, comprising administering to a mammal in need of such treatment or prevention a CCR1 receptor antagonizing effective amount of a compound of formula I, or a pharmaceutically acceptable salt thereof.
The following reaction Schemes illustrate the preparation of the compounds of the present invention. Unless otherwise indicated a, b, c, d, e, j, R1, R2, R3 and R4 in the reaction Schemes and the discussion that follow are defined as above.
R16 and R17 together with the nitrogen to which they are attached is selected from the group consisting of amino, amino(C1-C6)alkylcarbonylamino, (C1-C6)alkylamino(C1-C6)alkylcarbonylamino ((C1-C6)alkyl)2amino(C1-C6)alkylcarbonylamino, acetylamino(C1-C6)alkylcarbonylamino, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylcarbonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylcarbonylamino, cyanoguanidino(C1-C6)alkylcarbonylamino, (C1-C6)alkylcyanoguanidino(C1-C6)alkylcarbonylamino, ((C1-C6)alkyl)2cyanoguanidino(C1-C6)alkylcarbonylamino, aminocarbonyl(C1-C6)alkylcarbonylamino, aminocarbonylamino(C1-C6)alkylcarbonylamino, (C1-C6)alkylaminocarbonylamino(C1-C6)alkylcarbonylamino ((C1-C6)alkyl)2aminocarbonylamino(C1-C6)alkylcarbonylamino, (C2-C9)heteroaryl(C1-C6)alkylcarbonylamino, (C2-C9)heterocycloalkyl(C1-C6)alkylcarbonylamino, aminosulfonyl(C1-C6)alkylcarbonylamino, hydroxy(C1-C6)alkylureido, (amino(C1-C6)alkylureido, (C1-C6)alkylamino(C1-C6)alkylureido, ((C1-C6)alkyl)2amino(C1-C6)alkylureido, (C2-C9)heterocycloalkyl(C1-C6)alkylureido, (C2-C9)heteroaryl(C1-C6)alkylureido, aminosulfonyl(C1-C6)alkylureido, aminocarbonyl(C1-C6)alkylureido, (C1-C6)alkylaminocarbonyl(C1-C6)alkylureido, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkylureido, acetylamino(C1-C6)alkylureido, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylureido, carboxy(C1-C6)alkylureido, halo(C1-C6)alkylsulfonylamino, amino(C1-C6)alkylsulfonylamino, (C1-C6)alkylamino(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2amino(C1-C6)alkylsulfonylamino, acetylamino(C1-C6)alkylsulfonylamino, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylsulfonylamino, ureido(C1-C6)alkylsulfonylamino, (C1-C6)alkylureido(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2ureido(C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylsulfonylamino, cyanoguanidino(C1-C6)alkylsulfonylamino (C1-C6)alkylcyanoguanidino(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2cyanoguanidino(C1-C6)alkylsulfonylamino, aminocarbonyl(C1-C6)alkylsulfonylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkylsulfonylamino, aminosulfonylamino, (C1-C6)alkylaminosulfonylamino, ((C1-C6)alkyl)2aminosulfonylamino, aminocarbonyl(C1-C6)alkylamino(C1-C6)alkylsulfonylamino, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylsulfonylamino (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylsulfonylamino, cyanoguanidino, (C1-C6)alkylcyanoguanidino, ((C1-C6)alkyl)2cyanoguanidino, (C2-C9)heterocycloalkylcyanoguanidino, (C2-C9)heteroarylcyanoguanidino, (C2-C9)heterocycloalkyl(C1-C6)alkylcyanoguanidino, (C2-C9)heteroaryl(C1-C6)alkylcyanoguanidino, amino(C1-C6)alkylcyanoguanidino, (C1-C6)alkylamino(C1-C6)alkylcyanoguanidino, ((C1-C6)alkyl)2amino(C1-C6)alkylcyanoguanidino, aminocarbonyl(C1-C6)alkylcyanoguanidino, (C1-C6)alkylaminocarbonyl(C1-C6)alkylcyanoguanidino, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkylcyanoguanidino, hydroxy(C1-C6)alkylamino, aminocarbonyl(C1-C6)alkylamino, carboxy(C1-C6)alkylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkylamino, aminosulfonyl(C1-C6)alkylamino, (C2-C9)heteroaryl(C1-C6)alkylamino, acetylamino(C1-C6)alkylamino, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylamino, (C1-C6)alkylamino, ((C1-C6)alkyl)2amino, (C6-C10)arylamino, (C6-C10)aryl(C1-C6)alkylamino, amino(C1-C6)alkylamino, (C2-C9)heterocycloalkylamino, (C2-C9)heteroarylamino, (C3-C10)cycloalkyl(C1-C6)alkyl)amino, (C1-C6)alkylcarbonylamino, (C1-C6)alkoxycarbonylamino, (C2-C6)alkenylcarbonylamino, (C3-C10)cycloalkylcarbonylamino, (C6-C10)arylcarbonylamino, (C2-C9)heterocycloalkylcarbonylamino, halo(C1-C6)alkylcarbonylamino, (C1-C6)alkoxy(C1-C6)alkylcarbonylamino, (C1-C6)alkoxycarbonyl(C1-C6)alkylcarbonylamino, ((C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino, ((C1-C6)alkoxycarbonyl)((C1-C6)alkyl)amino, (C1-C6)alkylsulfonylamino, (C3-C10)cycloalkylamino, ureido, (C1-C6)alkylureido, (C6-C10)arylureido, ((C6-C10)aryl)2ureido, (C6-C10)aryl(C1-C6)alkylureido, halo(C1-C6)alkylureido, ((C1-C6)alkyl)((C6-C10)aryl)ureido, ((C1-C6)alkyl)2ureido, halo(C1-C6)alkylcarbonylureido, glycinamido, (C1-C6)alkylglycinamido, aminocarbonylglycinamido, (C1-C6)alkoxy(C1-C6)alkylcarbonylglycinamido, (aminocarbonyl)((C1-C6)alkyl)glycinamido, ((C1-C6)alkoxycarbonyl(C1-C6)alkylcarbonyl)((C1-C6)alkyl)glycinamido, ((C1-C6)alkoxycarbonylamino(C1-C6)alkylcarbonyl)glycinamido, (C6-C10)arylcarbonylglycinamido, ((C6-C10)arylcarbonyl)((C1-C6)alkyl)glycinamido, ((C6-C10)aryl(C1-C6)alkylaminocarbonyl)glycinamido, (C6-C10)aryl(C1-C6)alkylaminocarbonyl)((C1-C6)alkyl)glycinamido, (C6-C10)arylaminocarbonylglycinamido and ((C6-C10)arylaminocarbonyl)((C1-C6)alkyl)glycinamido.
R18 and R19 together with the nitrogen to which they are attached is selected from the group consisting of (C2-C9)heteroaryl(C1-C6)alkylamino, (C2-C9)heterocycloalkyl(C1-C6)alkylamino, (C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylamino, ureido(C1-C6)alkylamino, (C1-C6)alkylureido(C1-C6)alkylamino, ((C1-C6)alkyl)2ureido(C1-C6)alkylamino, halo(C1-C6)alkylamino, aminosulfonyl(C1-C6)alkylamino, (C1-C6)alkylaminosulfonyl(C1-C6)alkylamino, carboxy(C1-C6)alkylamino, (C1-C6)alkoxycarbonyl(C1-C6)alkylamino, cyano(C1-C6)alkylamino, aminocarbonyl(C1-C6)alkylamino, acetylamino(C1-C6)alkylamino, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkylamino, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylamino, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylamino, cyanoguanidino(C1-C6)alkylamino, (C1-C6)alkylcyanoguanidino(C1-C6)alkylamino, ((C1-C6)alkyl)2cyanoguanidino(C1-C6)alkylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylamino, ureido(C1-C6)alkylamino, (C1-C6)alkylureido(C1-C6)alkylamino, ((C1-C6)alkyl)2ureido(C1-C6)alkylamino, aminocarbonyloxy(C1-C6)alkylamino, acetylamino(C1-C6)alkylcarbonylamino, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylcarbonylamino, aminocarbonyl(C1-C6)alkylcarbonylamino, (C1-C6)alkylaminocarbonyl(C1-C6)alkylcarbonylamino, ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkylcarbonylamino, ureido(C1-C6)alkylcarbonylamino, (C1-C6)alkylureido(C1-C6)alkylcarbonylamino, ((C1-C6)alkyl)2ureido(C1-C6)alkylcarbonylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkylcarbonylamino, aminosulfonyl(C1-C6)alkylcarbonylamino, hydroxy(C1-C6)alkylamino(C1-C6)alkylcarbonylamino, (C1-C6)alkoxy(C1-C6)alkylamino(C1-C6)alkylcarbonylamino, (C2-C9)heterocycloalkyloxycarbonylamino, (C2-C9)heteroarylcarbonylamino(C1-C6)alkylcarbonylamino, (C2-C9)heterocycloalkylcarbonylamino(C1-C6)alkylcarbonylamino, cyanoguanidino(C1-C6)alkylcarbonylamino, cyano(C1-C6)alkylcarbonylamino, (C1-C6)alkylcarbonylamino(C1-C6)alkylamino-carbonylamino, amino(C1-C6)alkylaminocarbonylamino, (C1-C6)alkylamino(C1-C6)alkylaminocarbonyl amino, ((C1-C6)alkyl)2amino(C1-C6)alkylaminocarbonylamino, carboxy(C1-C6)alkylaminocarbonyl amino, aminocarbonyl(C1-C6)alkylaminocarbonylamino, (C1-C6) alkylcarbonylamino(C1-C6)alkylaminocarbonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylaminocarbonylamino, (C1-C6)alkoxycarbonyl amino(C1-C6)alkylaminocarbonylamino, (C2-C9)heterocycloalkyloxycarbonyl amino(C1-C6)alkylaminocarbonylamino, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylaminocarbonylamino, (C2-C9)heterocycloalkyl(C1-C6)alkylaminocarbonylamino, (C2-C9)heteroaryl(C1-C6)alkylaminocarbonylamino, ureido(C1-C6)alkylureido, (C1-C6)alkylureido(C1-C6)alkylureido, ((C1-C6)alkyl)2ureido(C1-C6)alkylureido, cyanoguanidino(C1-C6)alkylureido, amino(C1-C6)alkylsulfonylamino, (C1-C6)alkylamino(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2amino(C1-C6)alkylsulfonylamino, acetylamino(C1-C6)alkylsulfonylamino, (acetyl)((C1-C6)alkyl)amino(C1-C6)alkylsulfonylamino, ureido(C1-C6)alkylsulfonylamino, (C1-C6)alkylureido(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2ureido(C1-C6)alkylsulfonylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylsulfonylamino, cyanoguanidino(C1-C6)alkylsulfonylamino, (C1-C6)alkyl(cyanoguanidino)(C1-C6)alkylsulfonylamino, ((C1-C6)alkyl)2(cyanoguanidino)(C1-C6)alkylsulfonylamino, aminocarbonyl(C1-C6)alkylsulfonylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkylsulfonylamino, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylsulfonylamino, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylsulfonylamino, aminosulfonylamino(C1-C6)alkyl, (C1-C6)alkylaminosulfonylamino, ((C1-C6)alkyl)2aminosulfonylamino(C1-C6)alkyl, cyanoguanidino, (C1-C6)alkyl(cyanoguanidino), ((C1-C6)alkyl)2(cyanoguanidino), (C2-C9)heterocycloalkyl(cyanoguanidino), (C2-C9)heterocycloalkyl(cyanoguanidino), (C2-C9)heteroaryl(cyanoguanidino), (C2-C9)heterocycloalkyl(C1-C6)alkyl(cyanoguanidino), (C2-C9)heteroaryl(C1-C6)alkyl(cyanoguanidino), amino(C1-C6)alkyl(cyanoguanidino), (C1-C6)alkylamino(C1-C6)alkyl(cyanoguanidino), ((C1-C6)alkyl)2amino(C1-C6)alkyl(cyanoguanidino), aminocarbonyl(C1-C6)alkyl(cyanoguanidino), (C1-C6)alkylaminocarbonyl(C1-C6)alkyl(cyanoguanidino), ((C1-C6)alkyl)2aminocarbonyl(C1-C6)alkyl(cyanoguanidino), (C2-C9)heterocycloalkyl, amino(C1-C6)alkylamino, (C1-C6)alkylamino(C1-C6)alkylamino, ((C1-C6)alkyl)2amino(C1-C6)alkylamino, (C2-C9)heteroarylamino, ureido(C1-C6)alkylamino, (C1-C6)alkylureido(C1-C6)alkylamino, ((C1-C6)alkyl)2ureido(C1-C6)alkylamino, (C1-C6)alkylsulfonylamino(C1-C6)alkylamino, (C1-C6)alkoxycarbonylamino(C1-C6)alkylamino, (C2-C9)heterocycloalkyloxycarbonylamino(C1-C6)alkylamino, (C2-C9)heteroaryloxycarbonylamino(C1-C6)alkylamino, aminocarbonyl(C1-C6)alkylamino, cyanoguanidino(C1-C6)alkylamino, (C2-C9)heteroaryl(C1-C6)alkylamino, (C2-C9)heterocycloalkylamino, (C1-C6)alkylcarbonylamino, halo(C1-C6)alkylcarbonylamino, (C1-C6)alkoxycarbonylamino, ureido, (C1-C6)alkylureido, ((C1-C6)alkyl)2ureido, amino, (C1-C6)alkylamino, (C3-C10)cycloalkylamino, ((C1-C6)alkyl)2amino, hydroxy(C1-C6)alkylamino, (C6-C10)arylamino, (C6-C10)aryl(C1-C6)alkylamino, (C1-C6)alkylcarbonylamino, (C6-C10)arylcarbonylamino, ((C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino, (C3-C10)cycloalkyl(C1-C6)alkyl)amino, (C1-C6)alkoxycarbonylamino, (C1-C6)alkoxycarbonyl(C1-C6)alkylcarbonylamino, ((C1-C6)alkoxycarbonyl)((C1-C6)alkyl)amino, (C1-C6)alkylsulfonylamino, ((C1-C6)alkylsulfonyl)((C1-C6)alkyl)amino, (C6-C10)arylsulfonylamino, ((C6-C10)arylsulfonyl)((C1-C6)alkyl)amino, (C2-C9)heterocycloalkylamino, (C2-C9)heteroarylamino, halo(C1-C6)alkylamino, (C6-C10)arylamino, (C6-C10)aryl(C1-C6)alkylamino, (aminocarbonyl(C1-C6)alkylamino, ((C1-C6)alkylaminocarbonyl(C1-C6)alkylamino, (carboxy(C1-C6)alkyl)amino, ((C1-C6)alkoxycarbonyl(C1-C6)alkylamino, (amino(C1-C6)alkyl)amino, (hydroxy(C1-C6)alkylamino, ureido, (C1-C6)alkylureido, ((C1-C6)alkyl)2ureido, (C6-C10)arylureido, (C6-C10)aryl)2ureido, (C6-C10)aryl(C1-C6)alkylureido, halo(C1-C6)alkylureido, (halo(C1-C6)alkyl)((C1-C6)alkyl)ureido, ((C1-C6)alkoxycarbonyl(C1-C6)alkyl)ureido, and glycinamido. 
In reaction 1 of Preparation A, the compound of formula XXXV, wherein b is 0, 1 or 2, is converted to the corresponding compound of formula XXXIV by reacting XXXV with an ethyldiamine compound of the formula, (R3)j-ethyldiamine, in the presence of an aprotic solvent, such as diethylether. The reaction mixture is heated to reflux for a time period between about 1 hour to about 12 hours.
In reaction 2 of Preparation A, the compound of formula XXXIV is converted to the corresponding compound of formula XXXIII by reducing XXXIV with a reducing agent, such as sodium borohydride, in a refluxing protic solvent, such as ethanol.
In reaction 3 of Preparation A, the compound of formula XXXIII is converted to the corresponding compound of formula XXX by reacting XXXIII with a benzaldehyde compound of the formula 
in the presence of a base, such as triethylamine, and a reducing agent, such as sodium triacetoxyborohydride, in an aprotic solvent, such as 1,2-dichloroethane. The reaction mixture is stirred at room temperature for a time period between about 1 hour to about 4 hours, preferably about 2 hours.
In reaction 1 of Preparation B, the compound of formula XXII, wherein b is 0, 1 or 2, is converted to the corresponding compound of formula XXI by reacting XXIII with a benzaldehyde compound of the formula 
in the presence of a base, such as triethylamine, a reducing agent, such as sodium borohydride and an aprotic solvent, such as 1,2-dichloroethane. The reaction is stirred, at room temperature, for a time period between about 1 hour to about 4 hours, preferably about 2 hours.
In reaction 2 of Preparation B, the compound of formula XXI is converted to the corresponding compound of formula XX by first reacting a compound of the formula 
wherein j is 0, 1 or 2, with 4-methyl morpholine and isobutylchloroformate in the presence of a polar aprotic solvent, such as tetrahydrofuran, followed by reacting the intermediate so formed with the compound of formula XXI. The reaction mixture, so formed, is stirred overnight at room temperature.
In reaction 3 of Preparation B, the compound of formula XX is converted to the corresponding piperizine-2,5-dione compound of formula XIX by treating XX with trifluoroacetic acid in the presence of a polar aprotic solvent, such as methylene chloride. The reaction is stirred, at room temperature, for a time period between about 1 hour to about 4 hours, preferably about 2 hours.
In reaction 4 of Preparation B, the compound of formula XIX is converted to the corresponding compound of formula XVIII by reducing XIX with a reducing agent, such as lithium aluminum hydride. The reaction is conducted at a temperature between about xe2x88x92100xc2x0 C. to about 10xc2x0 C., preferably about 0xc2x0 C., for a time period between about 10 minutes to about 90 minutes, preferably about 40 minutes.
In reaction 1 of the Preparation C, the compound of formula XXV is converted to the corresponding compound of formula XXIV by reacting XXV with an amine of the formula, NHR18R19, wherein R18 and R19 are each independently selected from hydrogen, a nitrogen containing (C2-C9)heterocycloalkyl or (C2-C9)heteroaryl group, or (C1-C6)alkyl optionally substituted by hydroxy, aminocarbonyl, (C1-C6)alkylaminocarbonyl, ((C1-C6)alkyl)2carbonyl, carboxy, (C1-C6)alkylsulfonylamino, (C1-C6)alkoxycarbonylamino, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl, (C6-C10)alkoxy, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl, (C1-C6)alkylcarbonylamino, ((C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino, cyano, ureido, (C1-C6)alkylureido, ((C1-C6)alkyl)2ureido, cyanoguanidino, (C1-C6)alkylcyanoguanidino and ((C1-C6)alkyl)2cyanoguanidino, or R18 and R19 are taken together with the nitrogen to which they are attached to form a (C2-C9)heteroaryl or (C2-C9)heterocycloalkyl group, in the presence of a polar aprotic solvent, such as methylene chloride. The reaction mixture is stirred, at room temperature, for a time period between about 1 hour to about 24 hours, preferably about 12 hours.
In reaction 2 of Preparation C, the compound of formula XXIV is converted to the corresponding compound of formula XXIII by reacting XXIV with thiophenol in the presence of a base, such as sodium hydride, and a polar aprotic solvent, such as dimethylformamide. The reaction is heated to reflux for a time period between about 1 hour to about 10 hours, preferably about 4 hours.
In reaction 3 of Preparation C, the compound of formula XXV is converted to the corresponding compound of formula XXXVIII by reacting XXV with sodium cyanate in the presence of pyridine and a polar aprotic solvent, such as acetonitrile. The reaction is stirred, at room temperature, for a time period between about 2 hours to about 18 hours, preferably about 10 hours. An amine of the formula, H2Nxe2x80x94C(O)xe2x80x94NR18R19, is then added and the reaction mixture so formed is stirred, at room temperature, for a time period between about 2 hours to about 24 hours, preferably about 8 hours
In reaction 4 of Preparation C, the compound of formula XXXVIII is converted to the corresponding compound of formula XXXVII according to the procedure described above in reaction 2 of Preparation C.
In reaction 1 of Scheme 1, the compound of formula XXX is converted to the corresponding compound of formula X by reacting XXX with a compound of the formula, A-(X)c-(Y)d-A, wherein A is chloro or bromo, in the presence of a base, such as triethylamine, and a polar aprotic solvent, such as methylene chloride. The reaction is stirred at a temperature between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., for a time period between about 15 minutes to about 90 minutes, preferably about 30 minutes.
In reaction 2 of Scheme 1, the compound of formula X is converted to the corresponding compound of formula I by reacting X with a compound of the formula, H-(Z)e-R4 wherein e is 1 and Z is oxygen, in the presence of potassium carbonate, potassium iodide and an aprotic solvent, such as butanone. The reaction is heated to reflux for a time period between about 4 hours to about 8 hours, preferably about 6 hours.
In reaction 1 of Scheme 2, the compound of formula XXX is converted to the corresponding compound of formula I by reacting XXX with a compound of the formula, A-(X)c-(Y)d-(Z)e-R4, wherein A is chloro or bromo, in the presence of a base, such as triethylamine, and a polar aprotic solvent, such as methylene chloride. The reaction is stirred at a temperature between about xe2x88x9210xc2x0 C. to about 10xc2x0 C., for a time period between about 15 minutes to about 90 minutes, preferably about 30 minutes.
In reaction 1 of Scheme 3, the compound of formula X is converted to the corresponding compound of formula XII according to the procedure described above in reaction 2 of Scheme 1.
In reaction 2 of Scheme 3, the compound of formula XII is converted to the corresponding compound of formula XI by reacting XII with lithium hydroxide monohydrate in the presence of methanol, tetrahydrofuran and water. The reaction mixture is stirred overnight at room temperature.
In reaction 3 of Scheme 3, the compound of formula XI is converted to the corresponding compound of formula II, by reacting XI with an amine, in the presence of 4-dimethylaminopyridine, 1-(3-dimethylaminopropyl)-3-ethylcarbodiimine and a polar aprotic solvent, such as methylene chloride. The resulting reaction mixture is stirred overnight at room temperature.
In reaction 1 of Scheme 4, the compound of formula X is converted to the corresponding compound of formula XV according to the procedure described above in reaction 2 of Scheme 1.
In reaction 2 of Scheme 4, the compound of formula XV is converted to the corresponding compound of formula XIV by hydrogenating XV in the presence of a catalyst, such as platinum on carbon, and a polar protic solvent, such as ethanol. The reaction is carried out under a pressure between about 30 psi to about 40 psi, preferably about 35 psi, for a time period between about 15 minutes to about 1 hour, preferably 30 minutes.
In reaction 3 of Scheme 4, for urea formation, the compound of formula XIV is converted to the corresponding compound of formula V by first reacting XIV with 4-nitrophenyl chloroformate in the presence of a base, such as pyridine, and a polar aprotic solvent, such as methlyene chloride, followed by reacting the intermediate so formed with an amine. The reaction mixture, so formed, is allowed to stir overnight at room temperature. For sulfonamide formation, the compound of formula XIV is reacted with a sulfonyl chloride compound of the formula, R16xe2x80x94Cl, in the presence of a base, such as triethylamine, and a polar aprotic solvent, such as methylene chloride. The reaction is stirred overnight at ambient temperature. For cyanoguanidine formation, the compound of formula XIV is first treated with sodium hydride in an aprotic solvent, such as tetrahydrofuran, followed by reacting, the intermediate so formed with dimethyl-N-cyanodithio iminocarbonate. The reaction mixture so formed is heated to reflux overnight. The N-cyano-S-methyl-isothiourea intermediate is then reacted with an amine in the presence of a polar protic solvent, such as methanol. For amide formation, the compound of formula XIV is reacted with an acid, such as 3-tert-butoxycarbonylaminopropionic acid in the presence of N-methylmorpholine, O-benzotriazole-1-yl-N,N,N,xe2x80x2Nxe2x80x2-tetramethyluronium hexafluorophosphate and a polar aprotic solvent, such as methylene chloride.
In reaction 1 of Scheme 5, the compound of formula X is converted to the corresponding compound of formula XVI, wherein k is 0, 1, 2, 3 or 4, according to the procedure described above in reaction 2 of Scheme 1.
In reaction 2 of Scheme 5, the compound of formula XVI is converted to the corresponding compound of formula VII by reacting XVI with an amine of the formula, R16 R17N, wherein R16 and R17 are each independently hydrogen, a nitrogen containing (C2-C9)heterocycloalkyl or (C2-C9)heteroaryl group, or (C1-C6)alkyl optionally substituted by hydroxy, aminocarbonyl, (C1-C6)alkylaminocarbonyl, ((C1-C6)alkyl)2carbonyl, carboxy, (C1-C6)alkylsulfonylamino, (C1-C6)alkoxycarbonylamino, aminosulfonyl, (C1-C6)alkylaminosulfonyl, ((C1-C6)alkyl)2aminosulfonyl, (C6-C10)alkoxy, (C2-C9)heteroaryl, (C2-C9)heterocycloalkyl, (C1-C6)alkylcarbonylamino, ((C1-C6)alkylcarbonyl)((C1-C6)alkyl)amino, cyano, ureido, (C1-C6)alkylureido, ((C1-C6)alkyl)2ureido, cyanoguanidino, (C1-C6)alkylcyanoguanidino and ((C1-C6)alkyl)2cyanoguanidino, in the presence of a 10:1 ratio solution of dichloroethane/acetic acid. The reaction mixture is stirred, at room temperature, for a time period between about 30 minutes to about 2 hours, preferably about 1 hour. A reducing agent, such as sodium cyanoborohydride is than added to the mixture and the reaction is allowed to stir overnight at room temperature. When R16 and/or R17 is/are hydrogen, the compound of formula VII may further be reacted according to the procedure described above in reaction 3 of Scheme 4, to provide ureas, sulfonamides, cyanoguanidinos, or amides.
In reaction 1 of Scheme 6, the compound of formula X is converted to the corresponding compound of formula XXXIX according to the procedure described above in reaction 2 of Scheme 1.
In reaction 2 of Scheme 6, the compound of formula X is converted to the corresponding compound of formula XXXX according to the procedure described above in reaction 2 of Scheme 1.
In reaction 1 of Scheme 7, the acid compound of formula XXXVI is converted to the corresponding compound of formula XXXII by treating XXXVI with thionyl chloride neat or in an aprotic solvent, at room temperature, for a time period between about 1 hour to about 24 hours, preferably 1 hour. The acid chloride so formed is dissolved in a polar aprotic solvent with a compound of the formula, (H3CO)(H3C)NH.HCl, in the presence of an amine base, such as triethylamine. The reaction mixture is stirred, at room temperature, for a time period between about 1 hour to about 48 hours, preferably about 12 hours.
In reaction 2 of Scheme 7, the amide compound of formula XXXII is converted to the corresponding compound of formula XXXI by reacting XXXII with a (C2-C9)heteroaryl lithium reagent in the presence of a polar aprotic solvent at a temperature between about xe2x88x92100xc2x0 C. to room temperature, preferably about xe2x88x9278xc2x0 C. The resulting reaction mixture is stirred for a time period between about 1 hour to about 24 hours, preferably about 12 hours, at a temperature between about xe2x88x9278xc2x0 C. to about 50xc2x0 C., preferably about 20xc2x0 C.
Unless indicated otherwise, the pressure of each of the above reactions is not critical. Generally, the reactions will be conducted at a pressure of about one to about three atmospheres, preferably at ambient pressure (about one atmosphere).
The compounds of the formula I which are basic in nature are capable of forming a wide variety of different salts with various inorganic and organic acids. Although such salts must be pharmaceutically acceptable for administration to animals, it is often desirable in practice to initially isolate a compound of the formula I from the reaction mixture as a pharmaceutically unacceptable salt and then simply convert the latter back to the free base compound by treatment with an alkaline reagent, and subsequently convert the free base to a pharmaceutically acceptable acid addition salt. The acid addition salts of the base compounds of this invention are readily prepared by treating the base compound with a substantially equivalent amount of the chosen mineral or organic acid in an aqueous solvent medium or in a suitable organic solvent such as methanol or ethanol. Upon careful evaporation of the solvent, the desired solid salt is obtained.
The acids which are used to prepare the pharmaceutically acceptable acid addition salts of the base compounds of this invention are those which form non-toxic acid addition salts, i.e., salts containing pharmacologically acceptable anions, such as hydrochloride, hydrobromide, hydroiodide, nitrate, sulfate or bisulfate, phosphate or acid phosphate, acetate, lactate, citrate or acid citrate, tartrate or bitartrate, succinate, maleate, fumarate, gluconate, saccharate, benzoate, methanesulfonate and pamoate [i.e., 1,1xe2x80x2-methylene-bis-(2-hydroxy-3-naphthoate)] salts.
Those compounds of the formula I which are also acidic in nature, are capable of forming base salts with various pharmacologically acceptable cations. Examples of such salts include the alkali metal or alkaline-earth metal salts and particularly, the sodium and potassium salts. These salts are all prepared by conventional techniques. The chemical bases which are used as reagents to prepare the pharmaceutically acceptable base salts of this invention are those which form non-toxic base salts with the herein described acidic compounds of formula I. These non-toxic base salts include those derived from such pharmacologically acceptable cations as sodium, potassium, calcium and magnesium, etc. These salts can easily be prepared by treating the corresponding acidic compounds with an aqueous solution containing the desired pharmacologically acceptable cations, and then evaporating the resulting solution to dryness, preferably under reduced pressure. Alternatively, they may also be prepared by mixing lower alkanolic solutions of the acidic compounds and the desired alkali metal alkoxide together, and then evaporating the resulting solution to dryness in the same manner as before. In either case, stoichiometric quantities of reagents are preferably employed in order to ensure completeness of reaction and maximum product yields.
Compounds of the formula I and their pharmaceutically acceptable salts (hereinafter also referred to, collectively, as xe2x80x9cthe active compoundsxe2x80x9d) are potent antagonists of the CCR1 receptors. The active compounds are useful in the treatment or prevention of autoimmune diseases (such as rheumatoid arthritis, type I diabetes (recent onset), inflammatory bowel disease, optic neuritis, psoriasis, multiple sclerosis, polymyalgia rheumatica, uveitis, and vasculitis), acute and chronic inflammatory conditions (such as osteoarthritis, adult respiratory distress syndrome, Respiratory Distress Syndrome of infancy, ischemia reperfusion injury, and glomerulonephritis), allergic conditions (such as asthma and atopic dermatitis), infection associated with inflammation (such as viral inflammation (including influenza and hepatitis) and Guillian-Barre), chronic bronchitis, xeno-transplantation, transplantation tissue rejection, atherosclerosis, restenosis, HIV infectivity (co-receptor usage), and granulomatous diseases (including sarcoidosis, leprosy and tuberculosis).
The activity of the compounds of the invention can be assessed according to procedures know to those of ordinary skill in the art. Examples of recognized methods for determining CCR1 induced migration can be found in Coligan, J. E., Kruisbeek, A. M., Margulies, D. H., Shevach, E. M., Strober, W. editors: Current Protocols In Immunology, 6.12.1-6.12.3. (John Wiley and Sons, NY, 1991). One specific example of how to determine the activity of a compound for inhibiting migration is described in detail below.
The ability of compounds to inhibit the chemotaxis to various chemokines can be evaluated using standard 48 or 96 well Boyden Chambers with a 5 micron polycarbonate filter. All reagents and cells can be prepared in standard RPMI (BioWhitikker Inc.) tissue culture medium supplemented with 1 mg/ml of bovine serum albumin. Briefly, MIP-1xcex1 (Peprotech, Inc., P.O. Box 275, Rocky Hill N.J.) or other test agonists, were placed into the lower chambers of the Boyden chamber. A polycarbonate filter was then applied and the upper chamber fastened. The amount of agonist chosen is that determined to give the maximal amount of chemotaxis in this system (e.g., 1 nM for MIP-1xcex1 should be adequate).
THP-1 cells (ATCC TIB-202), primary human monocytes, or primary lymphocytes, isolated by standard techniques can then be added to the upper chambers in triplicate together with various concentrations of the test compound. Compound dilutions can be prepared using standard serological techniques and are mixed with cells prior to adding to the chamber.
After a suitable incubation period at 37 degrees centigrade (e.g. 3.5 hours for THP-1 cells, 90 minutes for primary monocytes), the chamber is removed, the cells in the upper chamber aspirated, the upper part of the filter wiped and the number of cells migrating can be determined according to the following method.
For THP-1 cells, the chamber (a 96 well variety manufactured by Neuroprobe) can be centrifuged to push cells off the lower chamber and the number of cells can be quantitated against a standard curve by a color change of the dye fluorocein diacetate.
For primary human monocytes, or lymphocytes, the filter can be stained with Dif Quik(copyright) dye (American Scientific Products) and the number of cells migrating can be determined microscopically.
The number of cells migrating in the presence of the compound are divided by the number of cells migrating in control wells (without the compound). The quotant is the % inhibition for the compound which can then be plotted using standard graphics techniques against the concentration of compound used. The 50% inhibition point is then determined using a line fit analysis for all concentrations tested. The line fit for all data points must have an coefficient of correlation (R squared) of  greater than 90% to be considered a valid assay.
All of the compounds of the invention that were tested had IC50 of less than 25 xcexcM, in the Chemotaxis assay.
The compositions of the present invention may be formulated in a conventional manner using one or more pharmaceutically acceptable carriers. Thus, the active compounds of the invention may be formulated for oral, buccal, intranasal, parenteral (e.g., intravenous, intramuscular or subcutaneous) or rectal administration or in a form suitable for administration by inhalation or insufflation. The active compounds of the invention may also be formulated for sustained delivery.
For oral administration, the pharmaceutical compositions may take the form of, for example, tablets or capsules prepared by conventional means with pharmaceutically acceptable excipients such as binding agents (e.g., pregelatinized maize starch, polyvinylpyrrolidone or hydroxypropyl methylcellulose); fillers (e.g., lactose, microcrystalline cellulose or calcium phosphate); lubricants (e.g., magnesium stearate, talc or silica); disintegrants (e.g., potato starch or sodium starch glycolate); or wetting agents (e.g., sodium lauryl sulphate). The tablets may be coated by methods well known in the art. Liquid preparations for oral administration may take the form of, for example, solutions, syrups or suspensions, or they may be presented as a dry product for constitution with water or other suitable vehicle before use. Such liquid preparations may be prepared by conventional means with pharmaceutically acceptable additives such as suspending agents (e.g., sorbitol syrup, methyl cellulose or hydrogenated edible fats); emulsifying agents (e.g., lecithin or acacia); non-aqueous vehicles (e.g., almond oil, oily esters or ethyl alcohol); and preservatives (e.g., methyl or propyl p-hydroxybenzoates or sorbic acid).
For buccal administration, the composition may take the form of tablets or lozenges formulated in conventional manner.
The active compounds of the invention may be formulated for parenteral administration by injection, including using conventional catheterization techniques or infusion. Formulations for injection may be presented in unit dosage form, e.g., in ampules or in multi-dose containers, with an added preservative. The compositions may take such forms as suspensions, solutions or emulsions in oily or aqueous vehicles, and may contain formulating agents such as suspending, stabilizing and/or dispersing agents. Alternatively, the active ingredient may be in powder form for reconstitution with a suitable vehicle, e.g., sterile pyrogen-free water, before use.
The active compounds of the invention may also be formulated in rectal compositions such as suppositories or retention enemas, e.g., containing conventional suppository bases such as cocoa butter or other glycerides.
For intranasal administration or administration by inhalation, the active compounds of the invention are conveniently delivered in the form of a solution or suspension from a pump spray container that is squeezed or pumped by the patient or as an aerosol spray presentation from a pressurized container or a nebulizer, with the use of a suitable propellant, e.g., dichlorodifluoromethane, trichlorofluoromethane, dichlorotetrafluoroethane, carbon dioxide or other suitable gas. In the case of a pressurized aerosol, the dosage unit may be determined by providing a valve to deliver a metered amount. The pressurized container or nebulizer may contain a solution or suspension of the active compound. Capsules and cartridges (made, for example, from gelatin) for use in an inhaler or insufflator may be formulated containing a powder mix of a compound of the invention and a suitable powder base such as lactose or starch.
A proposed dose of the active compounds of the invention for oral, parenteral or buccal administration to the average adult human for the treatment of the conditions referred to above (e.g., rheumatoid arthritis) is 0.1 to 1000 mg of the active ingredient per unit dose which could be administered, for example, 1 to 4 times per day.
Aerosol formulations for treatment of the conditions referred to above (e.g., rheumatoid arthritis) in the average adult human are preferably arranged so that each metered dose or xe2x80x9cpuffxe2x80x9d of aerosol contains 20 xcexcg to 1000 xcexcg of the compound of the invention. The overall daily dose with an aerosol will be within the range 0.1 mg to 1000 mg. Administration may be several times daily, for example 2, 3, 4 or 8 times, giving for example, 1, 2 or 3 doses each time.
The active agents can be formulated for sustained delivery according to methods well known to those of ordinary skill in the art. Examples of such formulations can be found in U.S. Pat. Nos. 3,538,214, 4,060,598, 4,173,626, 3,119,742, and 3,492,397.
The compounds of the invention can also be utilized in combination therapy with, but not limited to, other therapeutic agents such as with T-cell immunosuppressant agents such as rapamycin cyclosporin A and FK-506, with steroid sparing agents such as Cellcept(copyright), or with classical anti-inflammatory agents (e.g. cyclooxygenase/lipoxygenase inhibitors) such as tenidap, aspirin, acetaminophen, naproxen and piroxicam.
The following Examples illustrate the preparation of the compounds of the present invention. NMR data are reported in parts per million (xcex4) and are referenced to the deuterium lock signal from the sample solvent (deuteriochloroform unless otherwise specified). Commercial reagents were utilized without further purification. THF refers to tetrahydrofuran. DMF refers to N,N-dimethylformamide. Chromatography refers to column chromatography performed using 32-63 mm silica gel and executed under nitrogen pressure (flash chromatography) conditions. Low Resolution Mass Spectra (LRMS) were recorded on either a Hewlett Packard 5989(copyright), utilizing chemical ionization (ammonium), or a Fisons (or Micro Mass) Atmospheric Pressure Chemical Ionization (APCI) platform which uses a 50/50 mixture of acetonitrile/water with 0.1% formic acid as the ionizing agent. Room or ambient temperature refers to 20-25xc2x0 C. All non-aqueous reactions were run under a nitrogen atmosphere for convenience and to maximize yields. The names for the compounds of the invention were created by the Autonom 2.0 PC-batch version from Beilstein Informationssysteme GmbH (ISBN 3-89536-976-4).